US FDA grants accelerated approval to Janssen Pharmaâ„¢s first-in-class bispecific therapy, Talvey to treat heavily pretreated multiple myeloma

Friday, August 11, 2023,

The Janssen Pharmaceutical Companies of Johnson & Johnson announced that the US Food and Drug Administration (FDA) has granted accelerated approval of Talvey (talquetamab-tgvs), a first-in-class bispecific antibody for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody. This indication is approved under accelerated approval based on response rate and durability of response. Continued approval for this indication is contingent upon verification and description of clinical benefit in confirmatory trial(s).

Talvey is a bispecific T-cell engaging antibody that binds to the CD3 receptor on the surface of T cells and G protein-coupled receptor class C group 5 member D (GPRC5D) expressed on the surface of multiple myeloma cells, non-malignant plasma cells and healthy tissue such as epithelial cells in keratinized tissues of the skin and tongue. Talvey is approved as a weekly or biweekly subcutaneous (SC) injection after an initial step-up phase, offering physicians the flexibility to determine the optimal treatment regimen for patients.

“The clinically meaningful efficacy and safety profile observed with talquetamab in heavily pretreated patients in this clinical trial, which included patients treated with prior BCMA-targeted bispecific or CAR-T cell therapy, has been notable,” said Ajai Chari, M.D., Director of Multiple Myeloma Program, Professor of Clinical Medicine at the University of California, San Francisco.* “Patients at this stage of disease have a poor prognosis. Talquetamab as a first-in-class therapy is a new option for patients with this difficult-to-treat blood cancer.”

The talquetamab phase 2 MonumenTAL-1 study, which included patients who had received at least four prior lines of therapy and who were not exposed to prior T-cell redirection therapy (n=187), showed meaningful overall response rates (ORR).1 At the SC biweekly dose of 0.8 mg/kg, 73.6 percent of patients (95 percent Confidence Interval [CI], range, 63.0 to 82.4) achieved an ORR.1 With a median follow-up of nearly 6 (range, 0 to 9.5) months from first response among responders, 58 percent of patients achieved a very good partial response (VGPR) or better, including 33 percent of patients achieving a complete response (CR) or better. At the SC weekly dose of 0.4 mg/kg, 73.0 per cent of patients (95 per cent CI, range, 63.2 to 81.4) achieved an ORR. With a median follow-up of nearly 14 (range, 0.8 to 15.4) months from first response among responders, 57 percent of patients achieved a VGPR or better, including 35 per cent of patients achieving a CR or better. Responses were durable with a median duration of response not reached in the 0.8 mg/kg SC biweekly dose group and 9.5 months in the 0.4 mg/kg SC weekly dose group. Among patients receiving the 0.8 mg/kg SC biweekly dose, an estimated 85 per cent of responders maintained response for at least 9 months.

The MonumenTAL-1 study also included 32 patients who were exposed to prior bispecific antibody or CAR-T cell therapy (94 per cent B-cell maturation antigen [BCMA]-directed therapy) and had received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody, received Talvey at the 0.4 mg/kg SC weekly dose. With a median duration of follow-up of 10.4 months, 72 per cent of patients (95 percent CI, range, 53 to 86) achieved an ORR per an Independent Review Committee assessment, and an estimated 59 per cent of responders maintained response for at least 9 months.

The Safety Profile for Talvey includes a Boxed Warning for cytokine release syndrome (CRS) and neurologic toxicity including immune effector cell-associated neurotoxicity syndrome (ICANS); Warnings and Precautions include Oral Toxicity and Weight Loss, Infections, Cytopenias, Skin Toxicity, Hepatoxicity and Embryo-fetal toxicity. The most common adverse reactions (=20 per cent) are pyrexia, CRS, dysgeusia, nail disorder, musculoskeletal pain, skin disorder, rash, fatigue, weight decreased, dry mouth, xerosis, dysphagia, upper respiratory tract infection, diarrhoea, hypotension, and headache. The most common Grade 3 or 4 laboratory abnormalities (=30 percent) are lymphocyte count decreased, neutrophil count decreased, white blood cell decreased, and haemoglobin decreased.

"Although options for the treatment of multiple myeloma have expanded significantly in recent years, the disease remains incurable, and therefore, patients are in need of new treatment options,” said Michael Andreini, president and chief executive officer, Multiple Myeloma Research Foundation. “Today’s approval of talquetamab provides patients with a new treatment approach for relapsed or refractory disease that is a welcome addition to the myeloma community.”

“The approval of Talvey, our fifth innovative therapy and second bispecific antibody approved for the treatment of multiple myeloma, demonstrates our commitment to expanding our portfolio of medicines to help address unmet needs for patients who continue to face challenges with this complex hematologic malignancy,” said Peter Lebowitz, M.D., Ph.D., global therapeutic area head, oncology, Janssen Research & Development, LLC. “Our team of scientists never settles in their determination to discover and develop effective therapies. With the discovery of this new antigen, we continue to strive for research breakthroughs while remaining focused on delivering curative regimens in our commitment to eliminate cancer.”

Talvey is available only through a restricted programme called the Tecvayli and Talvey Risk Evaluation and Mitigation Strategy (REMS).

MonumenTAL-1 (phase 1: NCT03399799, phase 2: NCT04634552) is a phase 1/2 single-arm, open-label, multicohort, multicenter dose-escalation study involving over 300 patients. Phase 1 evaluated the safety and efficacy of Talvey in adults with relapsed or refractory multiple myeloma who received three or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. The study excluded patients who experienced T-cell redirection therapy within 3 months, prior Grade 3 or higher CRS related to any T-cell redirection therapy, an autologous stem cell transplant within the past 12 weeks, an allogenic stem cell transplant within the past 6 months, Eastern Cooperative Oncology Group (ECOG) performance score of 3 or higher, stroke or seizure within the past 6 months, CNS involvement or clinical signs of meningeal involvement of multiple myeloma, and plasma cell leukaemia, active or documented history of autoimmune disease (exception of vitiligo, resolved childhood atopic dermatitis or resolved Grave’s Disease that is euthyroid based on clinical and laboratory testing).

Phase 2 of the study evaluated the efficacy of Talvey in participants with relapsed or refractory multiple myeloma at the recommended phase 2 dose(s) (RP2Ds), established at SC 0.4 mg/kg weekly and 0.8 mg/kg every two weeks, respectively. Efficacy was based on overall response rate (ORR) and duration of response (DOR) as assessed by an Independent Review Committee using IMWG criteria.

Talvey is a bispecific T-cell engaging antibody that binds to the CD3 receptor expressed on the surface of T cells and G protein-coupled receptor class C group 5 member D (GPRC5D), a novel multiple myeloma target which is highly expressed on the surface of multiple myeloma cells and non-malignant plasma cells, as well as some healthy tissues such as epithelial cells of the skin and tongue.

Talvey is currently being investigated in combination and in sequence across all lines of multiple myeloma in studies with other bispecific antibodies as well as with existing standards of care. In addition to a phase 1/2 clinical study of Talvey for the treatment of relapsed or refractory multiple myeloma, Talvey is also being evaluated in combination studies (NCT04586426, NCT04108195, NCT05050097, NCT05338775) and in a randomized phase 3 study (NCT05455320).

In May 2021 and August 2021, Talvey was granted Orphan Drug Designation for the treatment of multiple myeloma by the US FDA and the European Commission, respectively. Talvey was also granted Breakthrough Therapy Designation from the US FDA in June 2022 for the treatment of adult patients with relapsed or refractory multiple myeloma who have previously received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody. The approval follows the FDA’s decision in February 2023 to initiate a Priority Review of the Biologics License Application (BLA) submitted in December 2022.

Multiple myeloma is an incurable blood cancer that affects a type of white blood cell called plasma cells, which are found in the bone marrow. In multiple myeloma, these plasma cells change, spread rapidly and replace normal cells in the bone marrow with tumours. Multiple myeloma is the third most common blood cancer and remains an incurable disease. In 2023, it is estimated that more than 35,000 people will be diagnosed with multiple myeloma in the US and more than 12,000 people will die from the disease. People living with multiple myeloma have a 5-year relative survival rate of 59.8 per cent. While some people diagnosed with multiple myeloma initially have no symptoms, most patients are diagnosed due to symptoms that can include bone fracture or pain, low red blood cell counts, tiredness, high calcium levels and kidney problems or infections.

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